Myosin regulatory light chain E22K mutation results in decreased cardiac intracellular calcium and force transients
Bibliographic record
Abstract
The glutamic acid to lysine mutation at the 22nd amino acid residue (E22K) in the human cardiac myosin regulatory light chain (RLC) gene causes familial hypertrophic cardiomyopathy (FHC) with a phenotype of midventricular obstruction and septal hypertrophy. Our recent histopathology results have shown that the hearts of transgenic E22K mice (Tg-E22K) resemble those of human patients, demonstrating enlarged interventricular septa and papillary muscles. In this study, we show no effect of the E22K mutation on the kinetics of mutated myosin in its ATP-powered interaction with fluorescently labeled single actin filaments compared to nontransgenic or transgenic wild-type (Tg-WT) control mice. Likewise, no change in cross-bridge dissociation rates (g(app)) was observed in freshly skinned papillary muscle fibers. In contrast, maximal force and ATPase were decreased approximately 20% in Tg-E22K skinned papillary muscle fibers and intracellular [Ca2+] and force transients were significantly decreased in intact papillary muscle fibers from Tg-E22K compared to Tg-WT mice. Moreover, energy metabolism measured in isolated working Tg-E22K mouse hearts perfused under conditions of physiologically relevant levels of metabolic demand was similar in Tg-E22K and control hearts before and after 20 min of no-flow ischemia. Our results suggest that the pathological response observed in the E22K myocardium might be triggered by mutation induced changes in the properties of the RLC Ca2+-Mg2+ site, the state of the Ca2+/Mg2+ occupancy and consequently the Ca2+ buffering ability of the RLC. By decreasing the affinity of the RLC for Ca2+, the E22K mutation most likely promotes a Mg2+-saturated RLC producing less force and ATPase than the Ca2+-saturated RLC of WT fibers. Decreased Ca2+ binding may also lead to faster Ca2+ dissociation kinetics in Tg-E22K intact fibers resulting in decreased duration and amplitude of [Ca2+] and force transients. These changes when placed in vivo would result in higher workloads and consequently cardiac hypertrophy.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".